Molecular Mechanisms of Protein Quality Control

The unfolding and aggregation of protein molecules represents a potential hazard to all living organisms, as is evident from the growing list of "protein folding diseases". To prevent inappropriate protein interactions, cells developed safeguard machineries that monitor the functionality of all proteins at any time. Central to this quality-control system are molecular chaperones and proteases, which channel damaged proteins into refolding and degradation pathways thereby reducing the amount of misfolded proteins. Strikingly, the involved players are not only critical to counteract proteotoxic stress. They also ensure the specific digestion and remodeling of target proteins that are present in a folded conformation. Elucidating the molecular mechanisms of respective protease and chaperone machines will help to better understand neurodegenerative diseases and to uncover strategies against mutations that effect protein integrity, as seen in cancer and ageing. Moreover, revealing differences in protein folding and degradation pathways between pathogens and their hosts will guide development of novel antibiotics. To this end, our studies concentrate on the following topics:

* Molecular machines rescuing aberrant proteins

* Regulatory proteolysis in cellular signaling

* Evolution of protein degradation marks

* Assembly of supra-molecular myo filaments

To characterize the mechanistic properties of the proteins of interest, we apply an integrative approach combining methods from structural biology, protein biochemistry and molecular cell biology. Key areas of expertise comprise

* Reconstitution of complex folding/degradation pathways in vitro

* Biochemical trapping and characterization of transient multi-protein complexes

* Protein crystallography, in particular of large, highly dynamic protein machineries

* Mass spectrometry, including various cross-linking approaches